Neurocognitive deficits are clearly associated with radiation therapy, particularly in children where they represent a major detrimental side effect of life-saving procedures. Long-standing changes in brain function have also been described in individuals exposed to radiation in the setting of radiological accidents (e.g Chernobyl). Although not as dramatic or life threatening as the classic syndromes associated with lethal and sub-lethal radiation exposure, radiation-induced changes in cognitive capacity will likely present a significant and life-long burden to individuals surviving a radiological accident or nuclear disaster. Accumulating evidence suggests that brain radiation injury leads to a persistent alteration in the brain's milieu, manifest in animal models over many months as activation of endogenous glial cells, recruitment of peripheral immune cells, and chronic elevation of cytokines, chemokines, and reactive oxygen and nitrogen species. We hypothesize that this neuroinflammatory milieu contributes to neurocognitive deficits, including inhibition of hippocampal neurogenesis and synaptic function. Therefore, a major goal of the proposed studies is to determine whether use of agents that inhibit neuroinflammation and/or production of ROS can mitigate radiation-induced changes in inflammatory cell populations, expression of cytokines, production of ROS, hippocampal neurogenesis, and neurocognitive effects. We will explore this hypothesis in adult mice under two exposure conditions (external and internal radiation) and in newly born animals where we expect the effects to be enhanced. We will also determine whether radiation exposed animals are primed for greater neurocognitive deficits following challenge with lipopolysaccharide, a second hit known to alter learning and memory. Finally, we will explore the possibility that total body irradiation combined with thermal burn exacerbates central nervous system effects. Specific outcomes of this project will include development of 4 mouse models for investigating the relationship between brain radiation injury and cognitive deficits, as well as testing of three drugs, each acting through a different mechanism to reduce the neuroinflammatory state and potentially restore cognitive capacity.